Plasma thyrotropin-releasing hormone, prolactin, thyrotropin, and thyroxine concentrations following the intravenous or oral administration of thyrotropin-releasing hormone.

In a further evaluation of the use of oral thyrotropin-releasing hormone (TRH) in puerperally lactating women, a radioimmunoassay for its measurement has been developed. Its concentration in plasma as well as that of prolactin (PRL), thyrotropin (TSH) and thyroxine (T4) were measured following either intravenous or oral administration of TRH. Basal concentrations of TRH in 14 normally cycling women ranged from less than 5 to 17 pg/ml. Two luteal phase studies produced peaks in plasma TRH 5 to 10 minutes after 100 micrograms of TRH administered intravenously with a return to basal concentrations within 2 to 3 hours. In 10 normally menstruating women, ingestion of 10 mg of TRH orally resulted in plasma TRH which peaked at 423 +/- 123 pg/ml (standard error of the mean) at 30-minutes. Plasma PRL, TSH, and T4 also increased and remained slightly elevated at 4 hours. These 8-hour studies were performed in a puerperal lactating woman who had ingested 10 mg of TRH orally twice a day for 7 days prior to blood sampling. TRH concentrations declined throughout each day while TSH rose slightly in the first 1 to 2 hours but remained within normal limits. The prolonged administration of 10 mg of TRH orally twice daily to three puerperally lactating women resulted in elevations in plasma TRH 2 to 3 hours following hormone administration, yet no significant increases in plasma TSH were observed. Both endogenous TRH and TSH were measured before and after 22 nursing events in nine puerperally lactating women. There was no change in the concentration of either substance and all values were similar to those obtained in normally menstruating women.     

Thyrotrophin-releasing hormone--a lactation-promoting agent?

OBJECTIVE--To study the lactational and hormonal responses to nasal administration of thyrotrophin-releasing hormone (TRH) in puerperal women with inadequate lactation. DESIGN--Prospective randomized double-blind placebo-controlled study. SUBJECTS--19 puerperal women with inadequate lactation (less than 50% of normal milk yield) on the 5th day postpartum. INTERVENTIONS--10 women were allocated to receive TRH administered by a nasal spray of 1 mg, four times daily, between suckling episodes, for 10 consecutive days starting on day 6 postpartum. Nine women were allocated to receive placebo sprays. MAIN OUTCOME MEASURES--Daily milk yield, serum levels of prolactin and thyroid hormones. RESULTS--Before treatment all the women had significant prolactin responses to TRH and suckling stimuli. At the end of 10 days of treatment, milk yield increased significantly in the TRH group from a mean of 142.0 (SD 33.9) to 253.0 (SD 105.3) g/day (P = 0.014). There was no significant change in the placebo group. Basal prolactin levels increased from a mean of 117.4 micrograms/l (SD 45.2) to 173.3 micrograms/l (SD 55.5) (P less than 0.001) in the TRH group whereas in the placebo group prolactin levels decreased from 137.2 (SD 69.5) to 82.0 (SD 37.7) micrograms/l. A further rise in prolactin levels and milk yield was seen in seven women in the TRH group who received a second 10-day course of TRH treatment at their own request. There was no significant change in levels of thyroid stimulating hormone, thyroxine and triiodothyronine during treatment in either of the two treatment groups and no signs of hyperthyroidism. CONCLUSION--Repeated nasal TRH administration between suckling episodes may improve defective lactation.     

Effect of dexamethasone on prolactin secretion in late pregnancy.

It is established that PRL secretion is regulated by estrogens. Glucocorticoids, on the other hand, suppress estrogen secretion during pregnancy and may also inhibit PRL by direct hypothalamopituitary action. In this study PRL and estradiol were determined with specific radioimmunoassays in 14 women during gestational weeks 28 to 34 prior to, during, and following short-term intramuscular dexamethasone administration (12, 8, and 4 mg on three consecutive days) used for prophylaxis of RDS in preterm infants. There were no significant alterations in PRL serum concentrations; estradiol showed a significant drop (P less than 0.001) during all 3 days of treatment, returning to the pretreatment level on posttreatment day 1. The PRL and TSH responses to 200 micrograms of intravenous TRH on day 2 or 3 of dexamethasone treatment in six women during late pregnancy were not inhibited. Short-term dexamethasone treatment with pharmacologic doses does not suppress the physiologic secretion and release of PRL or the release induced by TRH during late pregnancy.     

The effect of danazol on anterior pituitary function.

Danazol was given in a daily dose of 600 mg for 15 days to five postmenopausal women and five normal adult men. The basal levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), prolactin (PRL), and cortisol were determined for 3 days before treatment and during the last 3 days of treatment. A combined intravenous injection of 25 micrograms of gonadotropin-releasing hormone (GnRH) and 200 micrograms of thyrotropin-releasing hormone (TRH) was also given before and on the last day of treatment to each subject. Danazol reduces basal levels of FSH and LH and their cumulative response to GnRH but exercises no significant effect on either basal levels of TSH or PRL or their response to TRH, nor does it modify basal cortisol secretion.     

Study on the neuroendocrinological control of prolactin release in early puerperium

The purpose of this study is to investigate the neuroendocrinological control mechanism of prolactin (PRL) acting on the hypothalamo-pituitary axis during early puerperium. The puerperal women consisted of three groups: the breast-feeding group (n = 39), the bromocriptine (BRC)-treated group (5 mg/day, n = 17) and naloxone-treated group (1 mg iv, n = 16). In each group, 10 mg metoclopramide (MCP), 500 micrograms TRH or 400 mg cimetidine was given intravenously. 1) The plasma PRL levels increased significantly after the injection of MCP, TRH and cimetidine. The peak values of delta PRL levels were 447.0 +/- 62.3 ng/ml after MCP, 278.3 +/- 65.1 ng/ml after TRH and 86.5 +/- 27.3 ng/ml after cimetidine. 2) This PRL increase after the injection of MCP and cimetidine was suppressed significantly by pretreatment with BRC. However, the PRL increase after TRH was not suppressed by pretreatment with BRC. 3) Naloxone had no significant effect on PRL response to MCP and TRH, since the plasma PRL levels rose significantly after the injection of MCP and TRH in the naloxone-treated group. These results revealed that there were different mechanisms of PRL release in MCP and TRH. Furthermore, the PRL releasing mechanism was influenced by histamine H2-receptor, but was not influenced by opioid peptide in early puerperium.     

Evaluation of dynamic pituitary function testing in patients with hyperprolactinemia on diagnosis of pituitary prolactin-secreting adenoma (author's transl)

Thirty hyperprolactinemic women were divided into four group according to radiological and computed tomographic findings of sella turcica as follows; sulpiride-induced (N = 7), functional (N = 6), microadenoma (N = 9) and macroadenoma (N = 8). It was measured the serum basal level of pituitary LH, FSH, PRL, TSH and GH, and the responsiveness to LH-RH, TRH, insulin administration, respectively. These values were compared to that during bromocriptine treatment (5mg/day, 2 weeks). Before and during treatment with bromocriptine, there were not significant changes of basal level of LH, FSH and TSH, and also the responsiveness to LH-RH administration in four group. In pretreatment period, PRL responsiveness to TRH was good in sulpiride-induced and functional groups, but decreased in microadenoma and macroadenoma groups. During bromocriptine treatment period, basal PRL level was significantly suppressed in three groups except sulpiride-induced group, and PRL responsiveness to TRH was good in three groups except macroadenoma group. These findings ae concluded as follows: 1) Mechanism of the disturbance of ovulation in hyperprolactinemia does not closely related to pituitary gonadotroph dysfunction. 2) Decreased PRL responsiveness to TRH (maximal fold increase: under 40%) is of diagnostic value of pituitary adenomas. 3) Difference of PRL responsiveness to TRH during treatment with bromocriptine is distinguishing the microadenoma from macroadenoma.     

Domperidone in defective and insufficient lactation

The clinical use of anti-dopaminergic drugs to stimulate plasma PRL levels, to induce lactogenesis and maintain an adequate lactation has been widely suggested, taking into consideration the main inhibitory role of hypothalamic dopamine on PRL secretion. We therefore studied the effects of domperidone (DOM), a direct anti-dopaminergic drug with a low tendency to be secreted in the milk and which does not cross the blood-brain barrier, on inducing lactogenesis in 8 puerperal women with a history of defective lactogenesis (group A) and inducing galactopoiesis in 9 puerperal women who showed 2 weeks after delivery an insufficient lactation (group B). A placebo treatment was performed in 7 and 8 puerperal women with the same characteristics of group A and B, respectively. PRL plasma levels were assayed in basal conditions and after suckling from the 2nd to the 5th day of puerperium in group A and through a 10-day treatment in group B. In both groups domperidone-treated subjects always showed baseline PRL levels and daily milk yield significantly higher than those of the placebo group (P less than 0.01). The lack of any side-effects and the positive results suggest a high usefulness of such a drug in inducing and/or maintaining successful breast feeding, which is at present considered so important for a healthy development of infants.     

Hormonal control of lactation

We studied the mechanism of normal lactation, especially the roles of prolactin (PRL) and oxytocin (OXT) in the initiation of lactation, the lactation in the women complicated with endocrinological disorders, and medical therapies for stimulation and suppression of lactation. The level of serum PRL increases as pregnancy progresses, and reaches to a peak on the day of delivery. Despite high PRL level, milk secretion does not appear during pregnancy, because the sex steroid hormones suppress binding of PRL to the receptor in the mammary gland. The initiation of milk secretion in puerperal women seems to be closely related to an increase in PRL levels induced by adequate suckling. In the mechanism of suckling-induced PRL increase, OXT from posterior pituitary seems to have an important role. Furthermore, the poor response of PRL to suckling was due to insufficient stimulation to the nipples by suckling because the size of nipples were relatively small in these mothers. The other mechanism involved in lactation is suckling-induced OXT secretion. OXT stimulates milk ejection. Anxiety or fear may inhibit the OXT release. We demonstrated that the number of pulsatile release of OXT by nursing was significantly decreased by the psychological stress induced by mental calculation. In the puerperal women with prolactinomas after surgery, the serum PRL level did not increase during pregnancy and milk secretion in puerperium was poor. In the puerperal women with diabetes mellitus, milk secretion was also poor. One of the causes may be related to the low PRL response to suckling stimuli. PRL stimulates milk yield in the mammary gland, but is not commercially available.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxytocin enhances thyrotropin-releasing hormone-induced prolactin release in normal menstruating women

The effects of oxytocin (OT) on basal thyrotropin-releasing hormone (TRH)-stimulated thyrotropin (TSH) and prolactin (PRL) secretion were evaluated in normal menstruating women during follicular, periovulatory, and luteal phases. Two different studies were performed. In one study, 15 subjects were treated with OT or saline; in the other study, 20 women were tested with TRH alone or in combination with OT. Results during follicular, periovulatory, and luteal phases were similar. OT did not produce any effect on basal serum TSH and PRL levels and on the TRH-stimulated TSH secretion, whereas it significantly enhanced the PRL response to TRH. At all examined phases during the menstrual cycle, the mean peak PRL response was reached within 20 minutes after TRH injection, and the peak was about three times higher than basal value when TRH was given alone and about four times when OT was present. These data suggest that in normal women OT is not involved in the control of basal and TRH-stimulated TSH secretion and of basal PRL release. In contrast, the enhancement of the TRH-induced PRL release suggests that OT plays a role in the control of the acutely stimulated PRL secretion. Because results were similar regardless of the phase of the menstrual cycle, estrogen and/or progesterone do not appear to be involved in the effect of OT on the TRH-induced PRL release.     

Prolactin response to thyrotropin-releasing hormone in women with infertility and/or randomly elevated serum prolactin levels

Infertile women with normal serum prolactin (PRL) levels have been known to establish a pregnancy after the use of bromocriptine, a dopamine agonist. These data imply that there may be a group of women with a slight but significant increase in PRL secretion that may have resulted in their infertility. This study evaluates the thyrotropin-releasing hormone (TRH)-induced PRL and thyroid-stimulating hormone (TSH) response in normal women (NL, n = 6), women with anovulation and/or inphase endometrial biopsies (AN/IN, n = 12), and women with histologic evidence of luteal phase deficiency (LPD, n = 12). Most of these women were found to have elevated serum PRL values on random testing. There was a statistically significant increase in PRL response at all time intervals after TRH between the NL and AN/IN groups compared with the group with LPD on the basis of repeated measures analysis (P = 0.0013). There was no statistical difference in the TSH response between these three groups. Although the PRL response was statistically different, individual PRL response patterns were not diagnostic. It appears from these data that there is an increased PRL secretion in infertile women who have histological evidence of a LPD.     

Improvement of defective lactation by using oral metoclopramide.

An attempt has been made to pharmacologically enhance PRL secretion to improve lactation. Twenty-one puerperal women with past history of defective lactation and PRL levels under the normal range were studied for 4 weeks postpartum. Eleven patients who received orally 20 mg a day of metoclopramide showed persistently elevated basal levels of serum PRL during the four weeks' observation period. These women also had a good milk production and their infants did not need supplements. Ten women receiving placebo, however, showed an abrupt decrease in basal PRL levels, and this decrease persisted despite the continuation. Simultaneously a decline in the milk yield was observed and by the 14th postdelivery day milk production was minimal. The administration of metoclopramide at this moment to this group of poor lactating mothers produced an increase in serum PRL levels which presisted for the rest of the study. Metoclopramide also augmented the milk production so that these women were able to continue breast feeding their infants. Our preliminary results seem to prove that defective lactation associated with low prolactin levels (prolactipenia) can be treated by the manipulation of endogenous PRL secretion through the administration of metoclopramide or drugs which enhance PRL release.     

Metoclopramide and breast feeding: efficacy and anterior pituitary responses of the mother and the child

The purpose of this randomized, double-blind clinical study was to evaluate the efficacy of the antidopaminergic agent metoclopramide (MC) in the treatment of puerperal lactational insufficiency, and prolactin, TSH and free thyroxine responses of the mother and the child to this therapy. Therefore, 11 women received MC (10 mg 3 times daily orally) and 14 a placebo for 3 wk. MC increased the serum concentration of PRL from 57.5 + 45.5 U/l to 315.0 + 300.0 U/l (P less than 0.001), and the amount of daily milk yield in 8 women with established lactational deficiency rose from 285 + 75 ml to 530 + 162 ml (P less than 0.01) while the placebo was ineffective. Serum concentrations of TSH and free thyroxine did not change during either of the treatments. Serum concentrations of PRL, TSH and free thyroxine in the infants were similar in both groups and remained unchanged throughout the study. Our results suggest that MC is useful in the treatment of deficient puerperal lactation, and it does not stimulate the pituitary lactotropes or thyrotropes of the nursing infants.     

Effects of naloxone infusion on basal and breast-stimulation-induced prolactin secretion in puerperal women

The effects of naloxone infusion on plasma prolactin (PRL) levels and on the PRL response to mechanical breast emptying were investigated in a group of puerperal women, Five, 10, and 20 mg naloxone administered to women on days 2 to 3 of the puerperium produced no significant change in serum PRL. The same dose of naloxone had no significant effect on serum PRL response to mechanical breast stimulation in puerperal women. The results suggest that endogenous opioid peptides are not major modulators of PRL secretion in the puerperium.     

Prolactin and thyrotropin responses to nursing during the early puerperium

This study investigated the possible role of thyrotropin-releasing hormone (TRH) as a physiologic prolactin-releasing factor by measuring prolactin (PRL) and thyrotropin (TSH) responses to nursing. Eight women had serum samples drawn at 15-minute intervals for 1 hour while nursing during three separate periods in the hour while nursing during three separate periods in the first month postpartum. The samples were frozen and assayed in a single batch for PRL and TSH. Mean PRL levels during suckling increased greater than 50% over baseline values in all three sampling sessions. In contrast, suckling had no effect on circulating TSH. Our data fail to support the previously reported observation of a release of TSH in response to nursing and provide further indirect evidence that TRH is not responsible for the brisk release of PRL with suckling.     

Prolactin hyperstimulation in response to thyrotropin-releasing hormone in patients with endometriosis

In order to clarify the role of hyperprolactinemia as a possible cause of infertility in patients with endometriosis, baseline serum prolactin (PRL) concentrations and the PRL response to thyrotropin-releasing hormone (TRH) stimulation were measured in 14 infertile women with endometriosis and in 13 normal, fertile women. Baseline PRL concentrations were 2-fold greater in the endometriosis group than in normal subjects, but the mean values did not differ significantly. Following TRH administration, a significant increase in peak PRL concentrations was observed in patients with endometriosis (211.5 +/- 34.9 ng/ml) when compared with corresponding values in control subjects (117.1 +/- 14.9 ng/ml, P less than 0.05). This hypersecretory state was selective for PRL because no significant differences between the baseline and TRH-stimulated thyroid-stimulating hormone (TSH) concentrations or total serum thyroxine concentrations were observed. In summary, some infertile women with endometriosis exhibit a greater capacity for PRL secretion than normal women. These results suggest that relative hyperprolactinemia may be responsible for the infertility associated with endometriosis, and that PRL suppression may be indicated in these patients.     

Behavior of the hypothalamo-hypophyseal unit to stimulation with arginine, GnRH and TRH in patients with chronic uremia

In 11 women aged from 20 to 47 years (average age 33,1 years) with chronic uremia, treated by hemodialysis, a sequential stimulation test (SST) with 0.5 g arginine hydrochloride per kg body weight, 25 micrograms GnRH and 200 micrograms TRH was performed to examine the responsibility of the hypothalamo-pituitary unit. For evaluation of basal and stimulated secretion of PRL, LH, FSH, TSH, and HGH the corresponding serum levels were determined by RIA. 10 of the 11 women showed a galactorrhoea. No correlation between levels of PRL and creatinine could be found. Menstrual disorders in women with chronic uremia are discussed in the context of basal LH serum levels nearly always unphysiologically increased. In a few cases disturbances of basal secretion of TSH and HGH, respectively, could be observed.     

Relationship between luteal function and prolactin in infertile women with endometriosis

Luteal function in 44 infertile women with endometriosis were studied with reference to prolactin (PRL) and compared with 34 unexplained infertile women without endometriosis. To assess luteal function, serum progesterone (P4) levels were measured on the 3rd, 7th and 10th days of the luteal phase. On the 7th day, serum estradiol (E2) levels and PRL levels were also determined. The response of PRL secretion to TRH was examined at 30 and 60 after following TRH (500 micrograms, im.) administration. The incidence of hyperprolactinemia (basal PRL level greater than or equal to 25 ng/ml) and latent hyperprolactinemia (peak PRL level in TRH challenge test greater than or equal to 150 ng/ml) were 19% and 31%, respectively, in the endometriosis group and 14% and 33%, respectively in the control group. At the midluteal stage, serum P4 levels in endometriosis group were decreased significantly (p less than 0.05), whereas no difference was found between the serum E2 levels in the endometriosis group and the control. In the endometriosis group, there was no correlation between P4 and E2 levels and abnormal secretion of PRL such as hyperprolactinemia and latent hyperprolactinemia. These results indicate the close association of endometriosis with an inadequate luteal phase. However, it seems that the aberrant secretion of PRL has no relation to the impared luteal function in endometriosis.     

Exogenous melatonin enhances the TRH-induced prolactin release in normally cycling women: a sex-specific effect.

The aim of the present study was to analyze the effects of exogenous melatonin (MT) upon pituitary and adrenal responsiveness to releasing hormones in different phases of the menstrual cycle. We evaluated the response of FSH and LH to 100 micrograms gonadotropin releasing hormone, of TSH and prolactin (PRL) to 200 micrograms thyrotropin releasing hormone (TRH), and of cortisol to 10 micrograms ACTH 1-17. We studied eight young women with normal ovulatory cycles in the early follicular (days 5-7) and luteal (days 22-24) phases. Stimulation tests were performed at 18.00 in baseline conditions as well as 1 h after oral intake of exogenous MT (2 mg as a gelatine capsule). We did not observe any significant change in FSH, LH, TSH and cortisol responses to their respective releasing hormones in either phase of the cycle. PRL response to TRH was higher after MT in the follicular phase, when evaluated in terms of net increment and integrated area of response (p less than 0.02 versus baseline conditions for both variables). In the luteal phase, we recorded larger interindividual variability and higher responses after MT were observed in five out of eight subjects. These results suggest that MT may play a facilitatory role in the TRH-induced PRL release in women of reproductive age.     

The effect of thyrotropin-releasing hormone stimulation on serum levels of gonadotropins in women during the follicular and luteal phases of the menstrual cycle

Thyrotropin-releasing hormone (TRH) can stimulate the secretion of adenohypophyseal thyroid-stimulating hormone and prolactin (PRL). The effect of TRH on gonadotropin secretion has not been well defined. This study investigated the effect of TRH administration on the peripheral levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during the early follicular and midluteal phases of the menstrual cycle in five ovulatory, euthyroid, and normoprolactinemic women. Two hundred micrograms of TRH were administered intravenously on days 3 to 5 and on days 21 to 23 of the same cycle. LH and FSH were measured prior to and every 30 minutes for 2 hours following TRH injection. Ovulation was confirmed in all cycles by midluteal progesterone. All women had normal thyroid-stimulating hormone (TSH) and PRL responses to TRH stimulation in both cycle phases. Baseline and stimulated gonadotropin levels were analyzed by analysis of variance. Thirty minutes following TRH infusion, follicular and luteal levels of LH (mIU/ml, mean +/- standard error of the mean) significantly increased from 6.0 +/- 0.8 to 8.0 +/- 1.1 (P less than 0.005), and from 4.8 +/- 0.6 to 7.6 +/- 0.7 (P less than 0.005), respectively. Levels of FSH increased during both phases of the cycle, but the elevation was not statistically significant. These results suggest that TRH can stimulate gonadotrope secretion of LH, but not of FSH, in both the follicular and luteal phases of the cycle.     

Prolactin responsiveness to TRH in amenorrheic women with and without galactorrhea.

Sixty women were given intravenous injection of 200 microgram TRH to assess its diagnostic potential as a stimulus to PRL release. Following the administration of TRH, there was a prompt increase in serum PRL to 614.6%, to 296%, to 282.1%, and 34% in normal women, amenorrheic patients, non tumoral galactorrheic cases, and patients with pituitary tumors respectively. The TRH response above baseline of PRL levels was statistically significant in all groups, but the women with pituitary tumors which showed a blunted response. The per cent of increment of PRL levels after TRH was similar in amenorrheic women regardless the presence or not of galactorrhea; this increase was significantly greater than in patients with pituitary tumors (p less than 0.01). The per cent of increment above baseline of PRL was significantly greater in menstruating women than in amenorrheic patients (p less than 0.001). In basis of present data: 1) there is a diminished PRL secretion after TRH in amenorrheic women regardless the presence of galactorrhea or hyperprolactinemia; 2) a blunted response to TRH in hyperprolactinemic women may be indicative of a pituitary tumor.